P512: PRELIMINARY RESULTS OF VEN-A-QUI STUDY: A PHASE 1-2 TRIAL TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF AZACITIDINE OR LOW-DOSE CYTARABINE WITH VENETOCLAX AND QUIZARTINIB IN NEWLY DIAGNOSED
Authors: J. M. Bergua-Burgues, R. Rodríguez-Veiga, I. Cano, F. Vall-llovera, A. García-Guiñon, J. Gómez-Estruch, M. Colorado, I. Casas-Avilés, J. Esteve-Reyner, M. V. Verdugo, F. Ramos, M. Valero, E. Acuña-Cruz, B. Boluda, L. Torres-Miñana, J. Martínez-López, E. Barragán, R. Ayala, D. Martínez-Cuadrón, P. Montesinos
Journal: HemaSphere (2022)

Background: Venetoclax (VEN) combined with Azacitidine (AZA) or Low Dose Cytarabine (LDAC) has emerged as new therapeutic option for unfit acute myeloid leukemia (AML) patients (pts), but primary resistance is observed in roughly 40% of them, while relapses occur in the vast majority. We speculate that adding a FLT3-ITD inhibitor could improve the complete remission (CR) and overall survival (OS) rates in this setting. Aims: To explore the safety and efficacy of VEN-AZA or VEN-LDAC regimens in combination with Quizartinib (QUI) (VEN-A-QUI trial; EUDRACT2020-000406-28). Methods: The target population comprised newly diagnosed pts aged ≥ 60 years old unfit for intensive treatment, including those with secondary AML, with or without prior exposure to AZA. The Phase I consisted in two arms, one with AZA (Arm A) and the other with LDAC (Arm B) plus VEN combined with QUI to establish the recommended phase 2 dose (RP2D) of both triplets. Phase 1 scheme was based in 3 + 3 cohorts of patients observing cycle 1 dose limiting toxicities. Once established the RP2D the phase 2 comprised randomized 1:1 assignment of 60 patients (48 FLT3 wild type and 12 FLT3-ITD mut) to VEN-AZA-QUI vs. VEN-LDAC-QUI, comparing the CR/CRi rate of both arms. Secondary objectives were to evaluate the CR/CRi after cycle 1 and 4, compare OS and RFS between both triplets, quality of life, medical resources, exploration of biomarkers, and immune recovery. Results: Data cut-off for preplanned interim analysis included 57 pts screened and 45 enrolled, 16 in phase 1 and 29 in phase 2. Median age was 76,5 years (range 67-87), males/females (28/23). Previous MDS or MPN was present in 28 pts (59%); and 22 (48%) had previous treatment with AZA for MDS or MPN phase. We included 16 pts in phase 1, 9 with AZA and 7 with LDAC. RP2D of QUI was 60 mg in AZA arm and 40 mg in LDAC arm. No DLT was observed in arm B, and in arm A a brain hemorrhage after more than 40 days of thrombocytopenia at dose of 60 mg. The safety committee recommended performing an early (day 14-21) bone marrow assessment in cycle 1, leading to VEN interruption in case of aplastic morphology with grade 4 neutropenia or thrombocytopenia. No grade ≥3 related non-hematological adverse events (AEs) were noted during phase 1. The most frequent non-hematological serious AEs during phase 1 were infections (n=23), and gastrointestinal (n=20). No grade 3 QTc prolongation was observed. Objective responses were CR+CRh+CRi 7 pts (44%), PR 1 (6%), death 4 (25%), and resistance/progression 4 (25%). Twenty-nine pts (4 with FLT3-ITD mut) were enrolled in the phase 2 (15 in AZA and 14 in LDAC Arm). A median of 1 cycle (range 1-4) was administered at data cut-off, with best response among 24 evaluable pts: CR+CRh+CRi 10 (42%), MLFS in 3 (12%), PR 5 (21%), death 4 (17%), and resistance/progression 2 (8%). The overall response (CR+CRh+CRi+MLFS) was 54%. The more frequent non-hematological AEs were infections (n=35) and gastrointestinal (n=31). Two cardiac failures, 1 chest pain and 1 atrial fibrillation were noted in phase 2 (all of them unrelated to VEN or QUIZ). No grade 3 QTc prolongation was observed. Summary/Conclusion: This interim report shows an overall response rate of 54% using triplets (VEN-AZA-QUI or VEN-LDAC-QUI) for newly diagnosed unfit AML pts. However, substantial toxicity and early death cases were observed. Of note, 59% of enrolled pts had secondary AML, and 48% was exposed to AZA before inclusion. Final analyses with more pts and follow-up will clarify the efficacy and tolerability of these triplets.